Sorbitan esters as skin permeation enhancers

ABSTRACT

Skin permeation enhancer compositions are provided which increase the permeability of skin to transdermally administered pharmacologically active agents. The compositions contain a sorbitan ester in addition to the selected pharmacologically active agent, and may also contain a C 1  -C 4  aliphatic alcohol. Methods and transdermal drug delivery systems for using the compositions are also provided.

This application is a division of application Ser. No. 07/702,043 filedMay 17, 1991, now U.S. Pat. No. 5,122,383 issued Jun. 16, 1992.

TECHNICAL FIELD

The present invention relates generally to the transdermaladministration of pharmacologically active agents, and more particularlyrelates to methods and compositions for enhancing the permeability ofthe skin to such agents.

BACKGROUND

The delivery of drugs through the skin provides many advantages;primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorptionand metabolism encountered in oral treatment are avoided, and otherinherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possiblea high degree of control over blood concentrations of any particulardrug.

Skin is a structurally complex, relatively thick membrane. Moleculesmoving from the environment into and through intact skin must firstpenetrate the stratum corneum and any material on its surface. They mustthen penetrate the viable epidermis, the papillary dermis, and thecapillary walls into the blood stream or lymph channels. To be soabsorbed, molecules must overcome a different resistance to penetrationin each type of tissue. Transport across the skin membrane is thus acomplex phenomenon. However, it is the cells of the stratum corneumwhich present the primary barrier to absorption of topical compositionsor transdermally administered drugs. The stratum corneum is a thin layerof dense, highly keratinized cells approximately 10-15 microns thickover most of the body.

In order to increase skin permeability, and in particular to increasethe permeability of the stratum corneum (i.e., so as to achieve enhancedpenetration, through the skin, of the drug to be administeredtransdermally), the skin may be pretreated with a penetration enhancingagent (or "permeation enhancer", as sometimes referred to herein) priorto application of a drug. Alternatively, and preferably, a drug and apermeation enhancer are delivered concurrently.

The present invention is directed to a novel composition for enhancingthe penetration of pharmacologically active agents through skin, thecomposition based on a sorbitan ester as will be described herein. Thecomposition may or may not contain an aliphatic alcohol as an additionalcomponent. The sorbitan ester compositions of the invention have beenfound by the inventors herein to be particularly effective in enhancingthe penetration of pharmaceutically active agents through skin.

While there are a number of patents and publications available whichrelate to the transdermal administration of drugs and to skin permeationenhancer compositions, applicants are unaware of any art which suggeststhat sorbitan esters are useful as permeation enhancers in the absenceof additional permeation enhancing compounds or which describes thesorbitan ester/aliphatic alcohol compositions as described and claimedherein.

CITATION OF ART

The following references relate to one or more aspects of the presentinvention.

Skin permeation enhancers, generally: Various compounds for enhancingthe permeability of skin are known in the art. U.S. Pat. Nos. 4,006,218,3,551,554 and 3,472,931, for example, respectively describe the use ofdimethylsulfoxide (DMSO), dimethyl formamide (DMF) andN,N-dimethylacetamide (DMA) to enhance the absorption ofpharmacologically active agents through the stratum corneum. Othercompounds which have been used to enhance skin permeability include:decylmethylsulfoxide (C₁₀ MSO); diethylene glycol monoethyl ether;polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No.4,568,343); glycerol monolaurate (U.S. Pat. No. 4,746,515); propyleneglycol monolaurate; ethanol (e.g., as in U.S. Pat. No. 4,379,454);eucalyptol (U.S. Pat. No. 4,440,777 ; lecithin (U.S. Pat. No.4,783,450); the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Nelson Research & Development Co., Irvin, Cal.; see U.S.Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); propyleneglycol in combination with a fatty acid such as linoleic acid (EuropeanPatent Publication No. 261429); "cell envelope disordering compounds"such as methyl laurate or oleic acid in combination withN-(hydroxyethyl) pyrrolidone (U.S. Pat. No. 4,537,776); C₃ -C₄ diols(U.S. Pat. No. 4,552,872, European Patent Application Publication No.043738); or a binary system of oleic acid, oleins or oleyl alcohol incombination with a lower alcohol (U.S. Pat. No. 4,863,970).

Sorbitan analogs as permeation enhancers, specifically: T. Ogiso et al.,J. Pharmacobio-Dyn., 9:517-525 (1986), presents studies on percutaneousabsorption in vivo and the penetration in vitro of indomethacin.Sorbitan monooleate was tested as a permeation enhancer in combinationwith a dimethyl sulfoxide (DMSO) gel and was found to have no enhancingeffect. T. Ogiso et al., J. Pharm. Sci., 78(4):319-323 (1989), describesthe combined use of laurocapram and sorbitan monooleate in a permeationenhancer composition also containing a DMSO gel, for the transdermaladministration of indomethacin. W.-W. Shen et al., J. Pharm. Sci.,65(12):1780-1783 (1986), describes the effect of various nonionicsurfactants, including sorbitan monopalmitate and sorbitan trioleate, onthe percutaneous absorption of salicylic acid. As with the latter tworeferences, the sorbitan esters are used in conjunction with DMSO. U.S.Pat. No. 4,637,930 to Konno et al. describes a transdermal formulationfor the administration of nicardipine hydrochloride which contains amixed liquid composed of urea and an additional compound which may be asorbitan "middle chain" (6-12 carbon atom) fatty acid ester.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the invention to provide a methodfor enhancing the rate of penetration of a pharmacologically activeagent through the skin.

It is another object of the invention to provide such a method whichinvolves applying to a selected area of intact skin a therapeuticallyeffective amount of the selected pharmacologically active agent incombination with a permeation enhancer composition containing a sorbitanester.

It is still another object of the invention to provide such a methodwherein the permeation enhancer composition consists essentially of: (1)a sorbitan ester; or (2) a sorbitan ester in combination with analiphatic alcohol as will be described in detail herein.

It is a further object of the invention to provide a skin permeationenhancer composition comprising the pharmacologically active agent and apermeation enhancer composition which consists essentially of: (1) asorbitan ester; or (2) a sorbitan ester in combination with an aliphaticalcohol.

It is still a further object of the invention to provide a transdermalsystem in the form of a laminated composite designed to adhere to theskin. The composite contains, in addition to the selectedpharmacologically active agent to be administered, a permeation enhancercomposition containing a sorbitan ester, and, optionally, an aliphaticalcohol.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

In one aspect, the invention is a method for administering apharmacologically active agent transdermally so as to achieve relativelyhigh transdermal fluxes, by administering, through a predetermined areaof intact skin and for a predetermined period of time, (1) the agent,and (2) a permeation enhancer consisting essentially of a sorbitanester, or a sorbitan ester in combination with a C₁ -C₄ aliphaticalcohol. In a preferred embodiment, the skin permeation enhancer and thedrug are administered in a single composition. As the clearance rate ofmany drugs from the body is quite high, it is generally preferred thatadministration be substantially continuous throughout the time periodchosen for patch application.

In another aspect of the invention, a composition of matter is providedthat is useful for the delivery of a pharmacologically active agentthrough the skin, comprising:

(a) a therapeutically effective amount of the pharmacologically activeagent to be administered; and

(b) an amount of a permeation enhancer composition effective to enhancethe penetration of the pharmacologically active agent through the skin,wherein the enhancer consists essentially of a sorbitan ester or asorbitan ester combined with a C₁ -C₄ aliphatic alcohol.

In still another aspect of the invention, a therapeutic system isprovided for administering a drug transdermally, at relatively highfluxes as noted above, in the form of a skin patch. The skin patch ispreferably in the form of a matrix-type laminated composite containingan upper backing layer that is substantially impermeable to the drug,and at least one drug/enhancer reservoir, one of which forms the basalsurface of the device and is designed to adhere to the skin during use.The reservoir is a matrix which contains both the drug and a permeationenhancer as described above. Such a laminated composite preferablyincludes a strippable protective release liner laminated to the basalsurface of the drug reservoir. The release liner is a disposable elementdesigned to protect the exposed reservoir surface prior to use. In analternative embodiment, a transdermal therapeutic system is provided inthe form of a liquid reservoir-type laminated composite, e.g., asdescribed in commonly assigned U.S. Pat. No. 4,849,224 to Chang et al.,the disclosure of which is incorporated by reference herein.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic sectional view through a laminated matrix-typetransdermal system of the invention.

FIG. 2 is a schematic sectional view through a laminated liquidreservoir-type transdermal system of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present compositions, systems and methods of theinvention in detail, it is to be understood that this invention is notlimited to the particular drugs, sorbitan esters, aliphatic alcohols, orlaminate materials described herein as such may, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms "a," "an" and "the" include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a laminated structure containing "a drug" includes amixture of two or more drugs, reference to "an adhesive" includesreference to one or more of such adhesives, and reference to "a sorbitanester" includes reference to a mixture of two or more sorbitan esters.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

"Penetration enhancement" or "permeation enhancement" as used hereinrelates to an increase in the permeability of skin to apharmacologically active agent, i.e., so as to increase the rate atwhich the agent permeates into and through the skin. A "permeationenhancer" is a material which achieves such permeation enhancement, anda "penetration enhancing amount" of an enhancer as used herein means anamount effective to enhance skin penetration of a selected agent to adesired degree.

By "transdermal" drug delivery, applicant is using the term in itsconventional sense, i.e., to indicate delivery of a drug by passagethrough the skin and into the blood stream. By "transmucosal" drugdelivery, applicant intends delivery of a drug by passage of a drugthrough the mucosal tissue into the blood stream. "Topical" drugdelivery is used to mean local administration of a topical drug as in,for example, the treatment of various skin disorders. These terms willsometimes be used interchangeably herein, i.e., aspects of the inventionwhich are described in the context of "transdermal" drug delivery,unless otherwise specified, can apply to transmucosal or topicaldelivery as well. That is, the compositions, systems, and methods of theinvention, unless explicitly stated otherwise, should be presumed to beequally applicable with any one of these three modes of drug delivery.

The term "drug" or "pharmacologically active agent" as used herein isintended to mean a compound or composition of matter which, whenadministered to an organism (human or animal) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.In general, the terms include the therapeutic or prophylactic agents inall major therapeutic/prophylactic areas of medicine. Examples of drugsuseful in conjunction with the present invention include:anti-infectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antihelminthics; antiarthritics;antiasthmatic agents; anticholinergic agents; anticonvulsants;antidepressants; antidiabetic agents; antidiarrheals; antihistamines;anti-inflammatory agents, antimigraine preparations; anti-motionsickness drugs; antinauseants; antineoplastics; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimetics; xanthine derivatives; cardiovascularpreparations including calcium channel blockers and beta-blockers suchas pindolol and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary, peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; steroids; hypnotics; immunosuppressives; musclerelaxants; parasympatholytics; psychostimulants; sedatives; andtranquilizers. For purposes of the aforementioned definition, "drugs" asused herein also include locally administered topical medicaments suchas antibacterial agents, antifungals, antimicrobials, cutaneous growthenhancers, antipsoriatics, anti-acne medicaments, and the like.

"Carriers" or "vehicles" as used herein refer to carrier materialswithout pharmacological activity which are suitable for administrationin conjunction with the presently disclosed and claimed compositions,and include any such carrier or vehicle materials known in the art,e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or thelike. The carriers and vehicles suitable herein are "pharmaceuticallyacceptable" in that they are nontoxic, do not interfere with drugdelivery, and are not for any other reasons biologically or otherwiseundesirable. Examples of specific suitable carriers and vehicles for useherein include water, mineral oil, silicone, inorganic gels, aqueousemulsions, liquid sugars, waxes, petroleum jelly, and a variety of otheroils and polymeric materials.

By a "therapeutically effective" amount of a drug or pharmacologicallyactive agent is meant a nontoxic but sufficient amount of the drug oragent to provide the desired therapeutic effect.

The invention is thus in one embodiment a method for enhancing the rateof penetration of a pharmacologically active agent through the skin,wherein the method involves co-administration of the agent through apredetermined area of intact skin, and for a predetermined period oftime, the selected agent and a permeation enhancer consistingessentially of a sorbitan ester or a sorbitan ester in combination witha C₁ -C₄ aliphatic alcohol. The sorbitan esters which are useful inconjunction with the present invention have the structure ##STR1##wherein the substituent R₁ has the structure --O(CO)R', where R' isselected from the group consisting of saturated, mono-unsaturated,di-unsaturated and tri-unsaturated aliphatic hydrocarbon substituents of7 to 21 carbon atoms, preferably 11 to 21 carbon atoms, and may besubstituted with 1 to 3 hydroxyl groups. The substituents R₂ and R₃ maybe the same or different and are selected from the group consisting ofhydroxyl and --O(CO)R' as defined above. R₁, R₂ and R₃, may be, forexample, lauryl, myristyl, palmityl, stearyl, palmitoleyl, oleyl,linoleyl, linolenyl, or ricinoleyl esters, or the like. Exemplarysorbitan esters are long-chain sorbitan monoesters, wherein R₁ is asdefined above, R' is hydrocarbon of 11 to 21 carbon atoms, and R₂ and R₃are both hydroxyl. Particularly preferred compounds within the class ofsorbitan monoesters are sorbitan monooleate and sorbitan monolaurate.

In addition to a sorbitan ester, the permeation enhancer composition ofthe invention may also include a C₁ -C₄ aliphatic alcohol component.Examples of suitable alcohols within this class include ethanol,D-propanol, isopropanol, t-butanol, and mixtures thereof.

The method of delivery of the present compositions may vary, butnecessarily involves application of drug and enhancer to a selectedintact surface of the skin or other tissue for a period of timesufficient to provide the desired blood level of drug. The methodpreferably involves administration of drug and enhancer simultaneously,in a single composition, i.e., as an ointment, gel, cream, or the like,or may involve use of a drug delivery device as taught, for example, inU.S. Pat. Nos. 4,849,224, 4,983,395, 4,568,343, 3,797,494 or 3,742,951.

When the drug to be administered and the permeation enhancer asdescribed above are applied in the form of an ointment, gel, cream orthe like, the amount of drug contained within the composition willdepend on a variety of factors, including the desired rate of delivery,the desired dosage, the disease to be treated, the nature and activityof the drug, the desired effect, possible adverse reactions, the abilityand speed of the drug selected to reach its intended target, and otherfactors within the particular knowledge of the patient and thephysician. The amount of enhancer will typically be in the range of 0.1wt. % to 40 wt. % relative to the total composition, more preferably onthe order of about 2.5 wt. % to 15 wt. %. The composition may, inaddition to drug and enhancer, include one or more selected carriers orexcipients, and/or various agents and ingredients commonly employed indermatological ointments and lotions. For example, fragrances,opacifiers, preservatives, antioxidants, gelling agents, perfumes,thickening agents, stabilizers, surfactants, emollients, coloringagents, and the like may be present so long as they are pharmaceuticallyacceptable and compatible with the drug and enhancer.

A transdermal delivery system for the administration of a drug can beconstructed with the drug/enhancer composition described hereinabove.Preferred transdermal drug delivery systems for use herein are laminatedcomposites which contain one or more drug/permeation enhancerreservoirs, a backing layer and, optionally, one or more additionallayers (e.g., additional drug and/or enhancer reservoirs) as thoseskilled in the art of transdermal drug delivery will readily appreciate.FIG. 1 depicts an exemplary system, generally designated 10, that whenapplied to skin administers a selected pharmacologically active agent asoutlined above. System 10 is a laminated composite in which the toplayer 12 is a backing layer, its face forming the top surface of thecomposite. The drug reservoir, containing drug, enhancer as describedherein, and optional carriers or vehicles, is shown at 14, immediatelybelow and adjacent to the backing layer. Prior to use, the laminate alsoincludes a strippable protective release liner. In a preferredembodiment, as described in co-pending commonly assigned Ser. No.07/625,906, filed Dec. 10, 1990, and entitled "Method and Systems forAdministering Nitroglycerin Transdermally at Enhanced TransdermalFluxes," the release liner is in the form of two sheets 16a and 16b, thefirst sheet 16a partially overlapping the second sheet 16b. Additionalstructural layers and/or additional drug/enhancer reservoirs may also bepresent.

The drug reservoir is preferably comprised of a contact adhesive whichis a pressure-sensitive adhesive suitable for long-term skin contact. Itmust also be physically and chemically compatible with the drug andenhancer employed, and with any carriers or vehicles incorporated intothe drug/enhancer composition. Further, the adhesive selected for use asthe reservoir layer must be such that the drug and enhancer are at leastsomewhat soluble in the adhesive. The drug reservoir will generally bein the range of about 2 to 4 mils in thickness. Suitable adhesives foruse as the drug reservoir include polysiloxanes, polyacrylates,polyurethanes, tacky rubbers such as polyisobutylene, and the like.Particularly preferred contact adhesives for use as the drug reservoirherein are cross-linked acrylates (e.g., the Durotake® adhesives,available from National Starch & Chemical Co., New York, N.Y., or theGelvae® adhesives, available from Monsanto Co., St. Louis, Mo.).

The backing layer, which is, as shown, adhered to the drug reservoir andserves as the upper layer of the device during use, functions as theprimary structural element of the device. The backing layer is made of asheet or film of a preferably flexible elastomeric material that issubstantially impermeable to the drug/enhancer composition. The layerwill typically be on the order of 1.0 to about 4.0 mils in thickness,and is preferably of a material that permits the device to follow thecontours of the skin, such that it may be worn comfortably on any skinarea, e.g., at joints or other points of flexure. In this way, inresponse to normal mechanical strain, there is little or no likelihoodof the device disengaging from the skin due to differences in theflexibility or resiliency of the skin and the device. Examples ofpolymers useful for the backing layer herein are polyethylene,polypropylene, polyesters, polyurethanes, polyethylene vinyl acetate,polyvinylidene chloride, block copolymers such as PEBAX, and the like.The backing layer may also comprise laminates of one or more of theforegoing polymers.

The release liner is a disposable element which serves only to protectthe device prior to application. Typically, the release liner is formedfrom a material impermeable to the drug, vehicle, and adhesive, andwhich is easily stripped from the contact adhesive that serves as thedrug reservoir layer. Preferred release liners for use herein are thosewhich are generally suitable for use in conjunction withpressure-sensitive adhesives. Silanized polyester films are presentlypreferred.

In a preferred embodiment, as noted above, a two-part release liner isused, wherein a first strippable protective sheet (shown as 16a inFIG. 1) partially overlaps a second strippable protective sheet 16b,such that the area of overlap gives rise to a tab which extends from thebasal surface of the laminate, enabling ready removal of the strippablesheets from the reservoir layer.

The preferred laminated composites of the invention are as shown in FIG.1, having a backing layer, a drug reservoir, and a two-piece releaseliner; the drug reservoir contains a drug/enhancer composition asdescribed above, with the quantity of the drug therein, and with theremainder of the drug reservoir comprised of adhesive and optionalcarriers, vehicles or the like. If the drug is a hydrophobic materialsuch as a steroid, it is preferred that the quantity of drug containedwithin the reservoir is at "subsaturation" as described in detail inapplicants' copending, commonly assigned U.S. application Ser. No. 07626,685, filed Dec. 11, 1990, the disclosure of which is herebyincorporated by reference in its entirety. To use these laminatedcomposites, one is applied directly to the skin of a patient, to releasethe drug/enhancer composition to the skin, allowing the drug to permeateinto the circulation. The adhesive layer which serves as the drugreservoir should be in firm contact with the skin.

In general, such devices are fabricated using methods standard in theart, e.g., solvent-evaporation film casting in which all components ofthe drug/enhancer composition are admixed with the adhesive which willserve as the drug reservoir, and cast onto a substrate which is eitherthe backing layer or release liner. Other layers are then laminated tothis initial structure.

In an alternative embodiment, laminated composites containing drug in aliquid reservoir, as described in U.S. Pat. No. 4,849,224, may be used.As described in that patent, the disclosure of which is incorporated byreference herein, such devices shown generally at 18 in FIG. 2 arecomprised of an uppermost layer of a heat-sealable backing film 20having an inverted, cup-shaped recess that serves the reservoir 22 forthe drug-enhancer formulation. The underside of the outer edge of thebacking film carries a ring-shaped layer 24 of a pressure-sensitiveadhesive peripheral to the reservoir. Underlying the reservoir, justinward of the peripheral ring of adhesive, is a membrane layer 26 thatis permeable to the drug-enhancer formulation. A peel sealable innerliner 28 underlies membrane 26 and portions of backing film 20. Apeel-sealable release liner 30 covers the entire underside of theassembly and forms the basal surface of the device. Device 18 has a heatseal 32 between the membrane and backing film and a peelable(impermanent) heat seal 34 between the backing film and the inner liner28. An alternative liquid reservoir-type device which may be used inconjunction with the present compositions is described in U.S. Pat. No.4,983,395, also incorporated by reference herein.

Preferred daily dosages obtained with the present methods and systemswill, similarly, vary with the drug administered. The targeted dailydosage will depend on the individual being treated, the indicationaddressed, the length of time the individual has been on the drug, andthe like.

EXPERIMENTAL

The following examples are put forth so as to provide those withordinary skill in the art with a complete disclosure and description ofhow to formulate compositions and systems of the invention, and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers used (e.g., amounts, temperatures, etc.), but some experimentalerrors and deviations should be allowed for. Unless indicated otherwise,parts are parts by weight, temperatures are in degrees Centigrade, andpressure is at or near atmospheric.

Estradiol, norethindrone acetate, progesterone and pindolol wereobtained from Sigma Chemical Co., St. Louis, Mo. Polyacrylate adhesivesolutions were obtained from National Starch & Chemical Co., New Jersey(Durotake® 80-1194, 80-1054, 80-1070) and from Monsanto Corporation(Gelvae® 737). Sorbitan monooleate, sorbitan monolaurate and sorbitantrioleate Were all obtained from ICI Americas. Ethanol (USP 95%) wasobtained from Fisher Scientific.

Adhesive laminates were formulated by mixing the selected polyacrylatesolutions with drug and/or enhancer, followed by evaporation of solvent.The concentrated solution was cast onto the silanized surface of apolyester release liner (Release Technologies, 2-EST-A-S242M), using a10 mil gap Gardner knife. The cast adhesive was then dried at 80° C. for15 minutes in a convection oven to yield a final 0.050 inch thickadhesive coating. A 0.0075 inch thick low density polyethylene film(Schoeller Technical Paper Co., New York) was then laminated onto thedried adhesive surface to produce a three-layer transdermal matrixsystem construction.

The in vitro skin flux of the particular drugs tested was evaluatedacross human cadaver skin as described by Merrit and Cooper (J.Controlled Release (1984) 1:161) using a high-performance liquidchromatography (HPLC) assay. For these studies the release liner wasremoved from a previously cut section of the above transdermal matrixconstruction. The adhesive matrix was then positioned onto the stratumcorneum surface of heat separated human epidermis and the skin, with theadhering transdermal system, was then immediately mounted onto thediffusion cell. The steady state flux (μg/cm² /hr) of drug wasdetermined by linear regression analysis of the cumulative amount ofdrug permeating (μg/cm²) across the skin as a function of the time (hr).

EXAMPLE 1

The aforementioned procedure was used to evaluate the effect ofincreasing sorbitan ester levels on estradiol flux from acrylicadhesives. The sorbitan ester used was sorbitan monolaurate ("SML"); theacrylic adhesive used was Durotake® 80-1194 ("1194").

Results are set forth in Table I. As may be seen, the flux obtained wasfound to increase with increasing quantities of sorbitan monolaurate.

                  TABLE I                                                         ______________________________________                                        Effect of Increasing Sorbitan Monolaurate                                     Levels on Estradiol Flux from an Acrylic Adhesive                                            Estradiol Conc.                                                                           Flux                                               Enhancer System                                                                              (mg/ml)     (μg/cm.sup.2 /hr)                               ______________________________________                                        None           2 wt. %     0.26 ± 0.05                                      5 wt. % SML   2 wt. %     0.34 ± 0.09                                     10 wt. % SML   2 wt. %     0.43 ± 0.08                                     ______________________________________                                    

EXAMPLE 2

The procedure of Example 1 was followed to evaluate the effect ofsorbitan monooleate ("SMO") and sorbitan monolaurate on estradiol fluxfrom three different acrylic adhesive matrices, Durotake® 80-1194("1194"), Durotake® 80-1054 ("1054") and Durotake® 80-1070 ("1 070").All systems tested contained 4 wt. % estradiol. As may be deduced fromthe results set forth in the following table, the two sorbitan esterswere found to significantly increase flux in all three types of adhesivematrices.

                  TABLE II                                                        ______________________________________                                        Effect of Sorbitan Esters on Estradiol Flux                                   From Three Different Acrylic Adhesive Matrices                                Formulation    Flux (μg/cm.sup.2 /hr)                                      ______________________________________                                        1194           0.38 ± 0.36                                                 1194/15% SMO   1.69 ± 0.58                                                 1194/15% SML   0.96 ± 0.47                                                 1054           0.55 ± 0.12                                                 1054/15% SMO   0.95 ± 0.40                                                 1054/15% SML   1.07 ± 0.07                                                 1070           0.41 ± 0.07                                                 1070/15% SMO   0.68 ± 0.13                                                 1070/15% SMO   0.99 ± 0.31                                                 ______________________________________                                    

EXAMPLE 3

The procedure above was followed to prepare additional acrylic adhesivematrices containing estradiol (both with and without a sorbitan ester),so as to evaluate the effect of drug loading on estradiol flux. Theacrylic adhesive used was Durotak® 80-1070 ("1070"), and the sorbitanester used was sorbitan monooleate (present at subsaturation in allsystems tested). Results are set forth in Table III. Sorbitan Monooleatewas found to increase estradiol flux in both of the systems tested.

                  TABLE III                                                       ______________________________________                                        Effect of Drug Loading on Estradiol                                           Flux from an Acrylic Adhesive Matrix                                          With and Without Sorbitan Monooleate                                                             Skin 1     Skin 2                                          Formulation        (μg/cm.sup.2 /hr)                                                                     (μg/cm.sup.2 /hr)                            ______________________________________                                        1 wt. % estradiol, no enhancer                                                                   0.22 ± 0.08                                                                           0.34 ± 0.03                                  2 wt. % estradiol, no enhancer                                                                   0.56 ± 0.08                                                                           0.72 ± 0.09                                  1 wt. % estradiol, 5 wt. % SMO                                                                   0.43 ± 0.18                                                                           0.55 ± 0.07                                  2 wt. % estradiol, 5 wt. % SMO                                                                   1.00 ± 0.16                                                                           0.98 ± 0.08                                  ______________________________________                                    

EXAMPLE 4

The procedure above was followed by prepare additional acrylic adhesivematrices (Durotak® 80-1194) containing estradiol. One system wasprepared with sorbitan trioleate ("STO") as an enhancer, and a secondsystem was prepared without sorbitan trioleate. The flux obtained withthe sorbitan trioleate system was approximately 52% higher than thatobtained with the control system. Results are set forth in Table IV.

                  TABLE IV                                                        ______________________________________                                        Effect of Sorbitan Trioleate                                                  on Estradiol Flux (μg/cm.sup.2 /hr) from                                   an Acrylic Adhesive Matrix                                                    Formulation          Flux (μg/cm.sup.2 /hr)                                ______________________________________                                        4 wt. % estradiol, no enhancer                                                                     0.78 ± 0.13                                           4 wt. % estradiol, 10 wt. % STO                                                                    1.19 ± 0.13                                           ______________________________________                                    

EXAMPLE 5

The procedure above was followed to prepare acrylic adhesive matrices(Durotake® 80-1194 and 80-1054) containing 10 wt. % norethindroneacetate. Systems were prepared with and without 15 wt. % sorbitan ester;both sorbitan monooleate and sorbitan monolaurate were tested, as shownin Table V. As may be concluded from the results summarized in thetable, both sorbitan monooleate and sorbitan monolaurate significantlyincreased norethindrone acetate flux in both adhesive systems.

                  TABLE V                                                         ______________________________________                                        Effects of Sorbitan Esters on Norethindrone                                   Acetate Flux from Acrylic Adhesives Matrices                                                 Skin 1     Skin 2                                              Formulation    (μg/cm.sup.2 /hr)                                                                     (μg/cm.sup.2 /hr)                                ______________________________________                                        1194/no enhancer                                                                             0.21 ± 0.02                                                                           0.24 ± 0.02                                      1194/15% SMO   0.38 ± 0.20                                                                           0.31 ± 0.01                                      1194/15% SML   0.43 ± 0.09                                                                           0.60 ± 0.03                                      1054/no enhancer                                                                             --         0.27 ± 0.06                                      1054/15% SMO   --         0.40 ± 0.11                                      1054/15% SML   --         0.54 ± 0.06                                      ______________________________________                                    

EXAMPLE 6

The procedure above was followed to prepare acrylic adhesive matricesusing Gelvae® 737 ("737") containing 5 wt. % pindolol. Systems wereprepared with 15 wt. % sorbitan monooleate, 15 wt. % sorbitanmonolaurate, and 15 wt. % sorbitan trioleate, and compared with a systemnot containing any sorbitan ester. Again, the flux of drug was found tobe significantly higher for all of the systems formulated with thesorbitan esters, relative to the control. Results are set forth in TableVI.

                  TABLE VI                                                        ______________________________________                                        Effects of Sorbitan Esters on Pindolol                                        Flux from Acrylic Adhesive Matrices                                           Formulation    Flux (μg/cm.sup.2 /hr)                                      ______________________________________                                        737/no enhancer                                                                              0.23 ± 0.05                                                 737/15% SMO    0.55                                                           737/15% SML    0.75 ± 0.26                                                 737/15% STO    0.55 ± 0.19                                                 ______________________________________                                    

EXAMPLE 7

Flux of progesterone from ethanolic solutions of the drug was evaluatedas follows.

Ethanol/water/glycerin/sorbitan ester ointments were prepared assummarized in Table VII, and the flux of the drug therefrom evaluated.

                  TABLE VII                                                       ______________________________________                                        Progesterone Flux From Ethanolic                                              Solutions Containing Sorbitan Ester                                                                                 Flux                                    EtOH   H2O     Glycerin  SMO    SML   μg/cm.sup.2 /hr                      ______________________________________                                        --     88      10        2      --    0.61 ± 0.03                          --     88      10        --     2     1.21 ± 0.19                          60     30      10        --     --    6.29 ± 0.77                          60     28      10        2      --    13.04 ± 1.52                         60     28      10        --     2     10.33 ± 4.02                         ______________________________________                                    

The data summarized in Table 7 clearly demonstrates a synergisticenhancement for progesterone when ethanol is combined with sorbitanmonolaurate or sorbitan monooleate.

We claim:
 1. A laminated composite for administering a pharmacologicallyactive agent through a selected area of skin over a sustained timeperiod, comprising:(a) a backing layer that is substantially impermeableto the pharmacologically active agent, (b) a reservoir layer comprisingan adhesive polymer, the basal surface of the reservoir layer beingadapted to be adhered to the skin, and (c) a therapeutically effectiveamount of the pharmacologically active agent, and (d) a permeationenhancer which consists essentially of a sorbitan ester having thestructural formula ##STR2## wherein R₁ has the formula --O(CO)R', R' isselected from the group consisting of saturated, mono-unsaturated,di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, andR₂ and R₃ are independently selected from the group consisting ofhydroxyl and --O(CO)R'.
 2. The laminated composite of claim 1 whereinthe adhesive polymer is selected from the group consisting ofpolysiloxanes, polyacrylates, polyurethanes and tacky rubbers.
 3. Thelaminated composite of claim 1 wherein R' is selected from the groupconsisting of saturated, mono-unsaturated, di-unsaturated, ortri-unsaturated aliphatic hydrocarbon substituents of 11-21 carbon atomsoptionally containing 1-3 hydroxyl groups, and R₂ and R₃ are bothhydroxyl.
 4. The laminated composite of claim 3 wherein the sorbitanester is selected from the group consisting of sorbitan monooleate orsorbitan monolaurate.
 5. The laminated composite of claim 1 wherein thepharmacologically active agent is pindolol.
 6. The laminated compositeof claim 1 wherein the reservoir layer further includes apharmaceutically acceptable inert vehicle.
 7. A laminated composite foradministering a pharmacologically active agent through a selected areaof skin over a sustained time period, comprising:(a) a backing layerthat is substantially impermeable to the pharmacologically active agent,(b) a reservoir layer comprising an adhesive polymer, the basal surfaceof the reservoir layer being adapted to be adhered to the skin, and (c)a therapeutically effective amount of the pharmacologically activeagent, and (d) a permeation enhancer which consists essentially of asorbitan ester having the structural formula ##STR3## wherein R₁ has theformula --O(CO)R', R' is selected from the group consisting ofsaturated, mono-unsaturated, di-unsaturated, or tri-unsaturatedaliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionallycontaining 1 to 3 hydroxyl groups, and R₂ and R₃ are independentlyselected from the group consisting of hydroxyl and --O(CO)R', and a C₁-C₄ aliphatic alcohol.
 8. The laminated composite of claim 7 wherein theadhesive polymer is selected from the group consisting of polysiloxanes,polyacrylates, polyurethanes and tacky rubbers.
 9. The laminatedcomposite of claim 7 wherein R' is selected from the group consisting ofsaturated, mono-unsaturated, di-unsaturated, or tri-unsaturatedaliphatic hydrocarbon substitutents of 11-21 carbon atoms optionallycontaining 1-3 hydroxyl groups, and R₂ and R₃ are both hydroxyl.
 10. Thelaminated composite of claim 9 wherein the sorbitan ester is selectedfrom the group consisting of sorbitan monooleate or sorbitanmonolaurate.
 11. The laminated composite of claim 7 wherein the C₁ -C₄aliphatic alcohol is selected from the group consisting of ethanol,n-propanol, isopropanol, t-butanol, and mixtures thereof.
 12. Thelaminated composite of claim 7 wherein the pharmacologically activeagent is pindolol.
 13. A laminated composite for administering apharmacologically active agent through a selected area of skin over asustained time period, comprising:(a) a backing layer that issubstantially impermeable to the pharmacologically active agent; (b) anactive agent-permeable membrane, the backing layer and membrane defining(c) a reservoir therebetween which contains the pharmacologically activeagent and a permeation enhancer, said reservoir having a peripherysmaller than the backing layer and membrane such that portion of thebacking layer and membrane extends outwardly from the periphery of thereservoir; (d) a first peelable active agent formulation-impermeablelayer underlying the reservoir and a portion of said outwardly extendingportion of the backing layer and membrane; (e) an adhesive layer thatunderlies and covers the first peelable active agentformulation-impermeable layer and said portion of said outwardlyextending portion of the backing layer and membrane; (f) a secondpeelable active agent formulation-impermeable layer that underlies andcovers the adhesive layer; (g) a permanent heat seal about the peripheryof the reservoir between the backing layer and the membrane; and (h) apeelable heat seal underlying the permanent heat seal between thebacking and the first peelable layer, wherein the peel strengths betweenthe adhesive layer and the first and second peelable layers are greaterthan the force required to break the peelable heat seal, whereby whenthe second peelable layer is removed from the device, the peelable heatseal is broken and the first peelable layer and underlying portion ofthe adhesive layer is removed therewith, further wherein the permeationenhancer consists essentially of a sorbitan ester having the structuralformula ##STR4## wherein R₁ has the formula --O(CO)R', R' is selectedfrom the group consisting of saturated, mono-unsaturated,di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, andR₂ and R₃ are independently selected from the group consisting ofhydroxyl and --O(CO)R', or a sorbitan ester having the above describedstructural formula in combination with a C₁ -C₄ aliphatic alcohol.
 14. Alaminated composite for administering a steroid drug through a selectedarea of skin over a sustained time period, comprising:(a) a backinglayer that is substantially impermeable to the steroid drug, (b) areservoir layer comprising an adhesive polymer, the basal surface of thereservoir layer being adapted to be adhered to the skin, and (c) atherapeutically effective amount of the steroid drug, and (d) apermeation enhancer which consists essentially of a sorbitan esterhaving the structural formula ##STR5## wherein R₁ has the formula--O(CO)R', R' is selected from the group consisting of saturated,mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatichydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1to 3 hydroxyl groups, and R₂ and R₃ are independently selected from thegroup consisting of hydroxyl and --O(CO)R'.
 15. The laminated compositeof claim 14 wherein the adhesive polymer is selected from the groupconsisting of polysiloxanes, polyacrylates, polyurethanes, and tackyrubbers.
 16. The laminated composite of claim 14 wherein R' is selectedfrom the group consisting of saturated, mono-unsaturated,di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of11-21 carbons atoms optionally containing 1-3 hydroxyl groups, and R₂and R₃ are both hydroxyl.
 17. The laminated composite of claim 16wherein the sorbitan ester is selected from the group consisting ofsorbitan monooleate or sorbitan monolaurate.
 18. The laminated compositeof claim 14 wherein the steroid is selected from the group consisting ofestradiol, progesterone, norethindrone acetate, and mixtures thereof.19. The laminated composite of claim 14 wherein the reservoir layerfurther includes a pharmaceutically acceptable inert vehicle.
 20. Alaminated composite for administering a steroid drug through a selectedarea of skin over a sustained time period, comprising:(a) a backinglayer that is substantially impermeable to the steroid drug, (b) areservoir layer comprising an adhesive polymer, the basal surface of thereservoir layer being adapted to be adhered to the skin, and (c) atherapeutically effective amount of the steroid drug, and (d) apermeation enhancer which consists essentially of a sorbitan esterhaving the structural formula ##STR6## wherein R₁ has the formula--O(CO)R', R' is selected from the group consisting of saturated,mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatichydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1to 3 hydroxyl groups, and R₂ and R₃ are independently selected from thegroup consisting of hydroxyl and --O(CO)R', and a C₁ -C₄ aliphaticalcohol.
 21. The laminated composite of claim 20 wherein the adhesivepolymer is selected from the group consisting of polysiloxanes,polyacrylates, polyurethanes, and tacky rubbers.
 22. The laminatedcomposite of claim 20 wherein R' is selected from the group consistingof saturated, mono-unsaturated, di-unsaturated, or tri-unsaturatedaliphatic hydrocarbon substituents of 11-21 carbon atoms optionallycontaining 1-3 hydroxyl groups, and R₂ and R₃ are both hydroxyl.
 23. Thelaminated composite of claim 22 wherein the sorbitan ester is selectedfrom the group consisting of sorbitan monooleate or sorbitanmonolaurate.
 24. The laminated composite of claim 20 wherein the steroidis selected from the group consisting of estradiol, progesterone,norethindrone acetate, and mixtures thereof.
 25. The laminated compositeof claim 20 wherein the reservoir layer further includes apharmaceutically acceptable inert vehicle.
 26. A laminated composite foradministering a steroid drug through a selected area of skin over asustained time period, comprising:(a) a backing layer that issubstantially impermeable to the steroid; (b) an active agent-permeablemembrane, the backing layer and membrane defining (c) a reservoirtherebetween which contains the steroid drug and a permeation enhancer,said reservoir having a periphery smaller than the backing layer andmembrane such that a portion of the backing layer and membrane extendsoutwardly from the periphery of the reservoir; (d) a first peelablesteroid drug formulation-impermeable layer underlying the reservoir anda portion of said outwardly extending portion of the backing layer andmembrane; (e) an adhesive layer that underlies and covers the firstpeelable steroid drug formulation-impermeable layer and said portion ofsaid outwardly extending portion of the backing layer and membrane; (f)a second peelable steroid drug formulation-impermeable layer thatunderlies and covers the adhesive layer; (g) a permanent heat seal aboutthe periphery of the reservoir between the backing layer and themembrane; and (h) a peeleable heat seal underlying the permanent heatseal between the backing and the first peelable layer, wherein the peelstrengths between the adhesive layer and the first and second peelablelayers are greater than the force required to break the peelable heatseal, whereby when the second peelable layer is removed from the device,the peelable heat seal is broken and the first peelable layer andunderlying portion of the adhesive layer is removed therewith, furtherwherein the permeation enhancer consists essentially of a sorbitan esterhaving the structural formula ##STR7## wherein R₁ has the formula--O(CO)R', R' is selected from the group consisting of saturated,mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatichydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1to 3 hydroxyl groups, and R₂ and R₃ are independently selected from thegroup consisting of hydroxyl and --O(CO)R', or a sorbitan ester havingthe above described structural formula in combination with a C₁ -C₄aliphatic alcohol.
 27. The laminated composite of claim 26 wherein thesteroid is selected from the group consisting of estradiol,progesterone, norethindrone acetate, and mixtures thereof.